Thesis defense Cyrielle Jajkiewicz

The protein Rad (Ras-associated with diabetes), a member of the RGK family, plays a crucial role in regulating cardiac function by directly interacting with Ca_vβ, a subunit of the voltage-gated L-type calcium channel complex. The RRAD gene, responsible for synthesizing this protein, has been identified in a family affected by Brugada syndrome, all carrying the p.R211H variant. This syndrome is an inherited cardiac rhythm disorder that can lead to ventricular fibrillations and sudden cardiac death. The aim of this study is to assess the impact of the Rad protein in the development of Brugada syndrome in individuals carrying the p.R211H variant.This involves characterizing the effects of the mutation on electrical activity and cardiac structure in mice with an equivalent mutation (p.R210H) and exploring the molecular mechanisms of Rad regulating the Na_v1.5 sodium channel. The results demonstrate that Rad R211H induces a reduction in the protein expression of Rad, Na_v1.5, and Cx43, accompanied by a relocation of these proteins, contributing to electrical disturbances. This study represents the first evidence that Rad is part of a macromolecular complex including Na_v1.5 and Cx43, and its presence increases the membrane expression of Na_v1.5.